Method for the Dietary Management of Anxiety

ABSTRACT

A method for the dietary management of anxiety includes administering to a subject in need thereof water containing from 0.0002 to 0.0278 mol. % of isotopologue HOD, preferably, from 0.0178 to 0.0278 mol. % of isotopologue HOD.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of application Ser. No. 13/686,372 filed Nov. 27, 2012, which is incorporated herein by reference, and which claims priority on Russian patent application 2011149370, filed Dec. 5, 2011, which priority claim is repeated here.

FIELD OF THE INVENTION

The present invention is in the field of food industry and healthcare. More specifically, the present invention relates to method for the dietary management of anxiety.

BACKGROUND OF THE INVENTION

Major depression is a disorder characterized by a combination of symptoms such as lowered mood, loss of energy, loss of interest, feeling of physical illness, poor concentration, altered appetite, altered sleep and a slowing down of physical and mental functions resulting in a relentless feeling of hopelessness, helplessness, and guilt. National Institute of Mental Health estimates prevalence of major depressive disorder (MDD) as 6.7% of U.S. adult population, 56.8% of those with disorders are receiving treatment. Worldwide, MDD is a major cause of disability and premature death. Average-age-of onset of MDD is estimated as of 32 years old. The exact cause of MDD is not known. Present treatment of depression consists of psychotherapy, antidepressant drugs, or a combination of both. However, there are no special nutritional requirements related to the dietary management of patients with MDD.

Water is an essential nutrient. Total water intake includes drinking water, water in beverages, and water contained in food. The adequate intake for total water was set based on the median total water intake from U.S. survey data as 3.7 and 2.7 liters per day for men and women, respectively. Dietary Guidelines for Americans, 2005, U.S. Department of Health & Human Services. The natural water is a composition of nine water isotopologues (H₂ ¹⁶O, H₂ ¹⁷O, H₂ ¹⁸O, H¹⁶O, H¹⁷OD, H¹⁸OD, D₂ ¹⁶O, D₂ ¹⁷O, D¹⁸O) formed by stable isotopes of hydrogen (H and D) and oxygen (¹⁶O, ¹⁷O, ¹⁸O), wherein content of major water isotopologue H₂O (H₂ ¹⁶O) is 99.7317 molecular % (mol. %) and major deuterium-containing isotopologue HOD (H¹⁶OD) is 0.0311 mol. % (Vienna Standard Mean Ocean Water, VSMOW). Rothman et al., J. Quant. Spectrosc. Radiat. Transfer, 1998, 60, 665. Rothman et al., J. Quant. Spectrosc. Radiat. Transfer, 2003, 82, p. 9. Because of process of evaporation and condensation of ocean water, HOD levels in natural water slightly vary on Earth district. Only exclusion is natural water of Antarctica, which water contains HOD at levels of about 0.0178 mol. % (Standard Light Antarctic Precipitation, SLAP). A majority of people reside at Earth districts, where they consume natural water with HOD levels from 0.0280 to 0.0311 mol. %. On a calculation basis, when consume 2.7 and 3.7 liters of natural water per day, women and men consume no less than 0.8 and 1.0 ml of HOD as the obligate nutrient per day, respectively.

We discovered that HOD is a highly undesirable nutrient for a subject suffering from depression and HOD restriction may represent a special medically determined nutrient requirement, the dietary management of which cannot be achieved by the modification of the normal diet alone. Surprisingly, we found that mammals are highly sensitive to HOD levels in drinking water and even change of HOD content in drinking water within the range of its natural concentrations provides a significant effect on susceptibility to psychosocial stress and predisposition to the development of depression. Thus, the dietary management of major depression can be achieved by restriction of HOD daily consumption.

It is an object of the present invention is to provide a medical food for the dietary management of major depression comprising a water containing from 0.0002 to 0.0278 molecular % of isotopologue HOD.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a medical food for the dietary management of major depression comprising a water containing from 0.0002 to 0.0278 molecular % of isotopologue HOD.

In a preferred embodiment of the invention, the medical food comprises water containing from 0.0178 to 0.0278 molecular % of isotopologue HOD.

As used herein, the term “medical food” refers to a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of depression and/or anxiety, for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.

In a preferred embodiment of the invention, the medical food is specially formulated and processed as a drink product. Such drink products include, but are not limited by, drinking water, beverage, and liquid food.

As used herein, the term “major depression” (also known as major depressive disorder) refers to a mental disorder typically characterized by a lasting sad mood and/or loss of interest or pleasure in most activities.

As used herein, the term “isotopologue” is in accordance with IUPAC Compendium of Chemical Terminology 2nd Edition (1997) and refers to a molecular entity that differs only in isotopic composition (number of isotopic substitutions). Examples of such isotopologues include H₂ ¹⁶O, H₂ ¹⁷O, H₂ ¹⁸O, H¹⁶OD, H¹⁷OD, ¹H¹⁸OD, D₂ ¹⁶O, D₂ ¹⁷O, and D₂ ¹⁸O. The isotopologue H¹⁶OD is indicated in the present invention as HOD.

In preferred embodiments of the invention, HOD content in the water can be determined by methods well-known from the art. HOD levels can be directly measured by laser spectrometry. R. Van Trigt. R. van Trigt. Laser Spectrometry for Stable Isotope Analysis of Water Biomedical and Paleoclimatological Applications. 2002, Groningen: University Library Groningen. Also, HOD levels can be determined by conventional isotope mass-spectrometry as D/H ratio and re-calculated to HOD contents given that content of other deuterium-containing isotopologues in water is negligible as compared to HOD. For the reference, VSMOW water contains 0.00006 mol. % H¹⁸OD; 0.00001 mol. % H¹⁷OD; and less than 0.00001 mol. % for sum of isotopologues D₂ ¹⁶O, D₂ ¹⁷O, and D₂ ¹⁸O. The range 0.0002 to 0.0278 mol. % of isotopologue HOD in the water of the invention corresponds to the range of D/H ratio 1 to 139 ppm. The range 0.0178 to 0.0278 mol. % of isotopologue HOD in the water of the invention corresponds to the range of deuterium content 89 to 139 ppm.

In preferred embodiments of the invention, the water containing 0.0002 to 0.0278 mol. % of isotopologue HOD can be prepared by a variety of industrial procedures well-known from the art, e.g. vacuum distillation of natural water. The water containing 0.0178 to 0.0278 mol. % of isotopologue HOD can be obtained from rare natural sources (e.g. Antarctic precipitations) or prepared by a variety of industrial procedures well-known from the art, e.g. vacuum distillation of natural water.

In practicing the invention, the water containing 0.0002 to 0.0278 mol. % of isotopologue HOD may contain other water isotopologues at levels equal or other than in VSMOW standard of natural water, e.g. 0<H₂ ¹⁸O≦0.2000 mol. %; 0<H₂ ¹⁷O≦0.0370 mol. %; 0<H¹⁷O≦0.0270 mol. %; 0<H¹⁸OD≦0.0270 mol. %; 0<D₂ ¹⁸O≦0.0270 mol. %; 0<D₂ ¹⁷O≦0.0270 mol. %; 0<D₂ ¹⁸O≦0.0270 mol. %, and 0<H₂ ¹⁶O≦99.9998 mol. %.

The medical food of the invention may be prepared by well-known procedures using well-known optional ingredients. Such optional ingredients generally are used individually at levels from about 0.0005% to about 10.0%, preferably from about 0.005% to about 1.0% by weight of the composition. Examples of suitable optional ingredients include, but are not limited to, buffers, sweeteners, colorants, carriers, and etc.

In the preferred embodiments of the invention, the medical food is a liquid medical food specially formulated and manufactured in form of drinking water or beverage. The liquid medical food may be prepared by saturation of water containing 0.0002 to 0.0278 mol. % of isotopologue HOD with carbon dioxide or/and inorganic salts typically abandoned in natural drinking water. The examples of such salts include, but are not limited to, sodium chloride, sodium bicarbonate, calcium chloride, magnesium sulfate, etc.

In practicing the invention, the medical food can be administered orally for a period of one day or longer and in amounts as prescribed by a physician which manages the diet and/or provides medical supervision.

In practicing the invention, the medical food may be formulated as the drinking water or beverage that can be administered in amounts from 0.1 to 4.0 liters per subject per day.

In practicing the invention, the medical food may be consumed by mammals. Nonexclusive examples of such mammals include, but are not limited to, animals such as a dog, a cat, a horse, and a human. Preferably, the medical food is consumed by a human.

The following examples are presented to demonstrate the invention. The examples are illustrative only and are not intended to limit the scope of the invention in any way.

EXAMPLE 1

This example demonstrates the preparation of water samples with different contents of isotopologue HOD. The samples were prepared by mixing in certain proportions the conventional distilled water containing 0.0300 mol. % HOD and water containing 0.0002 mol. % HOD, wherein the last water was prepared by high-effective vacuum distillation of the conventional distilled water at 60° C. and pressure 0.2 bars using the distillation column of 10 m of height. HOD levels were measured by isotope laser spectroscopy using Los Gatos Research (LGR) Liquid Water Isotope Analyzer. Table 1 shows water samples comprising 0.0002 to 0.0278 mol. % of isotopologue HOD and D/H ratios corresponding therewith.

TABLE 1 Water samples Sample HOD content, mol. % D/H ratio, ppm Water No 1 0.0278 139 Water No 2 0.0240 120 Water No 3 0.0178 89 Water No 4 0.0002 1

EXAMPLE 2

This example demonstrates the medical food for the dietary management of major depression. The medical foods were formulated as mineralized drinking waters with HOD content as indicated in Table 2.

TABLE 2 Medical foods Ingredient (HOD, mol. %) Content, wt. % Medical food 1 Water No 1 (0.0278) 99.953 Calcium Chloride 0.015 Magnesium Chloride 0.007 Sodium Bicarbonate 0.025 Medical food 2 Water No 2 (0.0240) 99.953 Calcium Chloride 0.015 Magnesium Chloride 0.007 Sodium Bicarbonate 0.025 Medical food 3 Water No 3 (0.0178) 99.953 Calcium Chloride 0.015 Magnesium Chloride 0.007 Sodium Bicarbonate 0.025 Medical food 4 Water No 4 (0.0002) 99.953 Calcium Chloride 0.015 Magnesium Chloride 0.007 Sodium Bicarbonate 0.025

The medical foods No 1 through 4 were prepared by dissolution of Calcium Chloride, Magnesium Chloride, and Sodium Bicarbonate in Waters No 1 through 4, respectively, and subsequent bottling in bottles of 330 ml volume.

EXAMPLE 3

This example shows that deuterium-containing isotopologue HOD dose-dependently predisposes to the development of depression. Water samples of Table 3 were prepared by mixing in certain proportions of two equally mineralized waters having HOD level of 0.0184 mol. % (D/H ratio=92 ppm) and HOD level 0.0282 mol. % (D/H ratio=141 ppm).

TABLE 3 Water samples Water sample HOD content, mol. % D/H ratio, ppm W1 0.0184 92 W2 0.0240 120 W3 0.0258 129 W4 0.0282 141

Three-months-old male C57Bl/6 mice were randomly assigned by 15 animals per group and received W1, W2, W3, and W4 (Table 3) as drinking waters ad libitum for 14 days and then were tested for depressive-like behavior in a forced swim test and novel cage test, commonly accepted paradigms for pre-clinical testing of a depressive-like behavior. Antidepressant Imipramine (15 mg/kg per day) was administered to mice that were taken as positive control in the test. Results of forced swim test are presented in Table 4 as mean±SEM latency to floating (Latency) and duration of floating (Duration). As shown in Table 4, the increase in HOD levels in drinking water results in significant decrease in the latency to floating and increase in the duration of floating, meaning that deuterium-containing isotopologue HOD predisposes to the development of depression.

TABLE 4 Forced swim test Sample (HOD, mol. %) Latency, s Duration, s W1 (0.0184) 46 ± 6^(#)  89 ± 15^(#) W2 (0.0240) 48 ± 9^(#)  80 ± 14^(#) W3 (0.0258) 47 ± 11  86 ± 19^(#) W4 (0.0282) 31 ± 6* 128 ± 12* Imipramine 58 ± 4*^(#)  79 ± 8^(#)* *Differs significantly of W1 (p < 0.05). ^(#)Differs significantly of W4 (p < 0.05).

Results of novel cage test are presented in Table 5 as mean±SEM number of exploratory rearings in the new cage. As found, the increase in HOD levels in drinking water results in significant decrease in the number of exploratory rearings in the new cage, meaning that deuterium-containing isotopologue HOD predisposes to the development of depression.

TABLE 5 Novel cage test Sample (HOD, mol. %) Number, n W1 (0.0184) 35.0 ± 1.5^(#) W2 (0.0240) 35.5 ± 1.5^(#) W3 (0.0258) 33.0 ± 1.5 W4 (0.0282) 30.0 ± 1.0* Imipramine 34.0 ± 1.5^(#) *Differs significantly of W1 (p < 0.05). ^(#)Differs significantly of W4 (p < 0.05).

Thus, these results suggest that deuterium-containing water isotopologue HOD in drinking water predisposes to depressive-like behavior. Therefore, HOD is a very undesirable nutrient for subjects with major depressive disorder and HOD restriction may represent a special medically determined nutrient requirement, the dietary management of which cannot be achieved by the modification of the normal diet alone.

EXAMPLE 4

This example demonstrates that deuterium-containing isotopologue HOD predisposes to the development of anhedonia, the core symptom of depression. Young adult male C57Bl/6J mice received ad libitum waters W1 or W4 (Table 3) for one week prior the onset of stress and during the ten days of a chronic stress. Citalopram 15 mg/kg per day per os was used as the reference antidepressant drug. There was no difference between groups at baseline. At 10th day of the stress procedure, animals were tested on the sucrose preference, common test for assessment of anhedonia. Results are presented in Table 6 as mean±SEM percent of sucrose preference.

TABLE 6 Sucrose preference test Group (HOD, mol. %) Sucrose preference, % W1 (0.0184) 73.5 ± 3.0^(#) W4 (0.0282) 62.5 ± 2.0* Citalopram 70.0 ± 3.0^(#) *Differs significantly of W1 (p < 0.05). ^(#)Differs significantly of W4 (p < 0.05).

As shown in Table 6, the increase in HOD levels in drinking water results in significant decrease in sucrose preference, meaning that deuterium-containing isotopologue HOD predisposes to the development of anhedonia, the core symptom of depression. Therefore, HOD is a very undesirable nutrient for subjects with major depressive disorder and HOD restriction may represent a special medically determined nutrient requirement, the dietary management of which cannot be achieved by the modification of the normal diet alone.

EXAMPLE 5

This example demonstrates that deuterium-containing isotopologue HOD predisposes to the development of depression in elderly. Table 7 shows that sucrose preference in old C5Bl/6J mice is significantly decreased in comparison with young adult C5Bl/6J mice, meaning that normal aging induces spontaneous anhedonia in mice.

TABLE 7 Group Sucrose preference, % Young adult C57BI/6J mice (3 months old) 78.0 ± 2.5 Old C57B1/6J mice (18 months old) 60.6 ± 3.1* *Differs significantly of young adult mice (p < 0.05).

To estimate effect of HOD on anhedonia in elderly, 18 month old male C57Bl/6J mice received ad libitum waters W1 or W4 (Table 3) for 14 days. There was no difference between groups at baseline. At the end of the experiment, mice were tested in sucrose preference test. Results are presented in Table 8 as mean±SEM percent of sucrose preference. As found, the increase in HOD levels in drinking water results in significant decrease in sucrose preference, meaning that deuterium-containing isotopologue HOD predisposes to the development of anhedonia, the core symptom of major depression, in elderly.

TABLE 8 Sucrose preference test Group (HOD, mol. %) Sucrose preference, % W1 (0.0184) 81.3 ± 1.9 W4 (0.0282) 69.4 ± 4.4* *Differs significantly of W1 (p < 0.05).

To estimate effect of HOD on depressive-like behavior in elderly, 18 month old male C57Bl/6J mice received ad libitum waters W1 or W4 (Table 3) for 14 days. There was no difference between groups at baseline. At the end of the experiment, mice were tested in forced swim test. Results are presented in Table 9 as mean±SEM of latency to floating (Latency) and duration of floating (Duration). As found, the increase in HOD levels in drinking water results in decrease in the latency to floating and significant increase in the duration of floating, meaning that deuterium-containing isotopologue HOD predisposes to the development of depression in elderly.

TABLE 9 Forced swim test Group (HOD, mol. %) Latency, s Duration, s W1 (0.0184) 17.4 ± 4.2 126.7 ± 13.9 W4 (0.0282) 13.7 ± 3.1 186.7 ± 10.0* *Differs significantly of W1 (p < 0.05).

Therefore, HOD is a very undesirable nutrient for elderly subjects with depressive disorders and HOD restriction may represent a special medically determined nutrient requirement, the dietary management of which cannot be achieved by the modification of the normal diet alone. 

We claim:
 1. A method of the dietary management of anxiety consisting of administering to a subject in need thereof a water containing from 0.0002 to 0.0278 molecular % of isotopologue HOD.
 2. The method of claim 1, wherein the water contains from 0.0178 to 0.0278 molecular % of isotopologue HOD. 